AU597270B2 - A pharmaceutical composition for the treatment of high blood pressure - Google Patents

Abstract

The preparation contains an angiotensin converting enzyme inhibitor and a loop diuretic.

Description

597270 Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority SRelated Art: This document contains the a me;ndments made under Section 49 and is correct for n: ^''tirfg.

4 4; ro Na' o f Applicant: o oddress of Applicant 0 0 0 a Sactual Inventor; 4o HOECHST AKTIENGEJELLSCHAFT 45 Bruningstrasse. D-6230 Frankfurt/Main Federal Republic of Germany REINHARD BECKER, ROLF GEIGER, RAINER HENNING, VOLKER TEETZ and HANSJORG URBACH EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Address for Service Complete Speclfication for the invention entitled: A PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF HIGH BLOOD PRESSURE The following statement Is c full description of this invention, including the best method of performing it known to :'US

I,

-la- HOECHST AKTIENGESELLSCHAFT Dr.WS/gm HOE 85/F 184 A pharmaceutical composition for the treatment of high blood pressure It is known that the high blood pressure of patients with essential hypertension can be reduced using inhibitors of angiotensin converting enzyme (ACE inhibitors), such as captopril or enalapril (Therapiewoche 29 [1979] 7746; Lancet 2 [19813 543-546). However, a certain percentage of patients with essential hypertension do not respond to substances of this type (Drug Devel. Eval. 4 [19803 82-91).

It has been disclosed that the antihypertensive action of enalapril or captopril is potentiated by the addition of diuretically effective amounts of a diuretic of the thiazide type or analogous compounds (Brunner et al., Clin. Exp. Hypertension 2 C1980] 639-657; McGregor et al., Br. Med. J. 284 [1982] 693-696). It is generally assumed that this effect is based on stimulation by the diuretic of the renin-angiotensin system via a loss of salt and volume Chin et al., J. Pharm. Pharmacol.

S. 37 [1985] 105).

There is a report in Arzneim.-Forsch./Drug Res. 34 (II) C19843 1417-1425 of investigations into the cardiovascular action of 2-EN-E(S)-1-carboxy-3-phenylpropyl]-Lalanyl]-(1S,3S,5S)-2-azabicycloC3.3.03octane-3-carboxylic acid ("ramiprilate"). This entailed animals being pretreated with furosemide or piretanide for several days for the purpose of sodium depletion.

We have now found, surprisingly, that ACE inhibitors combined with loop diuretics in low dosage effectively lower blood pressure.

Thus the invention relates to pharmaceutical compositions containing I

L-U~

SI I 2 a) an angiotensin converting enzyme inhibitor or its physiologically tolerated salt, and b) a loop diuretic or its physiologically tolerated salt.

Examples of loop diuretics included within the meaning of the present invention are furosemide, bumetanide, ethacrynic acid, etozolin and piretanide. As is evident from the name, the main point of attack of these diuretics, which have a short but potent effect, is the loop of Henle (cf. Mutschler, ArzneimitteLwirkungen (Effects of drugs) 4th Edition, Stuttgart 1981, pages 486 and 487). Compounds of the formula I

R

2 R -R

(I)

H2NOS

COOH

in which R1 denotes chlorine or phenoxy,

R

2 denotes hydrogen, pyrrolidino or n-butylamino, and

R

3 denotes hydrogen or 2-furylmethylamino are particularly suitable examples.

Piretanide 'see formula II) 020

H

2

NO

2 S

COOH

is particularly preferred.

Suitable ACE inhibitors are described in, for example, US Patent 4,129,571, US Patent 4,154,960, US Patent 4,374,8?9, European Patent A-79,522, European Patent A- 79,022, European Patent A-49,658, European Patent ,1 I 44 a 4l 0 t 44 11 4 14 004 4 a4 O S S A-51,301, US Patent 4,454,292, US Patent 4,374,847, European Patent A-72,352, US Patent 4,350,704, European Patent A-50,800, European Patent A-46,953, US Patent 4,344,949, European Patent A-84,164, US Patent 4,470,972, European Patent A-65,301 and European Patent A-52,991.

A large proportion of the ACE inhibitors disclosed in the abovementioned publications can be described by the general formula V, ROOC CH N- C NH CH (CH -R (V) 19 110 6oo 7 R R 0 R COR in which n is 1 or 2, R denotes hydrogen, an optionally substituted aliphatic radical having 1 8 carbon atoms, an optionally substituted alicyclic radical having 15 3 9 carbon atoms, an optionally substituted aromatic radical having 6 12 carbon atoms, an optionally substituted araliphatic radical having 7 14 carbon atoms, 20 an optionally substituted alicyclic-aliphatic radical having 7 14 carbon atoms, a radical ORa or SR a in which Ra represents an optionally substituted aliphatic radical having 1 4 carbon atoms, represents an optionally substituted aromatic radical having 6 12 carbon atoms, or an optionally substituted heteroaromatic radical having 5 12 ring atoms,

R

6 denotes hydrogen, an optionally substituted aliphatic radical having 1 6 carbon atoms, an optionally substituted alicyclic radical having 3 9 carbon atoms, an optionally substituted alicyclic-aliphatic radical having 4 13 carbon atoms, an optionally substituted aromatic radical having T- -C -T 'i ,I 4 6 12 carbon atoms, an optionally substituted araliphatic radical having 7 16 carbon atoms, an optionally substituted heteroaromatic radical having 5 12 ring atoms, or the side chain, protected where necessary, of a naturally occurring a-amino acid, R and R8 are identical or different and denote hydrogen, an optionally substituted aliphatic radical having 1 6 carbon atoms, an optionally substituted alicyclic radical having 3 9 carbon atoms, an optionally substituted aromatic radical having 6 12 carbon atoms, an optionally substituted araliphatic radical having 7 16 carbon atoms, and 9 10 R and R together with the atoms carrying them, form a heterocyclic, meR-, bi- or tricyclic ring system having j 15 carbon atoms, particularly suitable 20 ring systems of this type being those of the following group: *o°o Tetrahydroisoquinoline decahydroisoquinoline octahydroindole octahydrocyclopenta[bJpyrrol 2-azaspiro[4.53decane 2 -azaspiroC4.43nonane 25 spiroE(bicyclo[2.2.13heptane)-2,3-pyrrolidine] spiro- E(bicyclo2.2.2.2octane)-2,3-pyrrolidine) 2-azatricycloE4.3.0.1 6 '93decane decahydrocyclohepta[b3pyrrol octahydroisoindole octahydrocyclopentaCc3pyrrol 2,3,3a,4,5,7a-hexahydroindole 2-azabicyclo[3.1.03hexane all of which can optionally be substituted.

However, the unsubstituted systems which have the following structural formulae are preferred.

II,

I M ,.,COOR 8

A

N-'-OOR

8 1

COOR

8

B

'COOR8 E I Q N> -COOR 8

C

COOR

8

COOR

8

COOR

8 I I

COOR

8

Q-COOR

8

K

Y COOR 8

I

S i I

COOR

8 For the compounds which have several chiral atoms, all the possible diastereomers are suitable as racemates or enantiomers, or mixtures of various diastereomers. The S configuration of the carbon atoms labelled with an asterisk is preferred.

Examples of very suitable ACE inhibitors of the formula V are those in which n is 1 or 2, Rdenotes hydrogen, alkyl having 1 8 carbon atoms, aLkenyL having 2 6 carbon atoms, cycloalkyL having 3 -9 carbon atoms, aryL which has 6 12 carbon atoms and can be mono-, dli- or trisubstituted by (Cl-C 4 a Lky L, (Cl-C 4 )-aLkoxy, hydroxyl, halogen, nitro, amino, aminomethyL, (Cl-C 4 )-aLkyLamino, di- (Cl-CO -aL kylamirno, (Cl-C 4 )-aL anoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyL, a~koxy having 1 -4 carbon atoms, aryLoxy which has 6 12 carbon atoms and can be substituted as described above for aryl, mono- or bicyclic heteroaryloxy which has 5 7 or 8 10 ring atoms respectively, 1 to 2 of these ring atoms being suLfur or oxygen atoms and/or 1 -4 of these ring atoms being nitrogen, and which can be~ substituted as described above for aryl, Amino-(Cl-C 4 )-aLkyL, (Cl-C 4 )-aLkanoyLamino-(cv'l-C 4 )-aLkyl, 0 0 (C 7 -Cl3)-aroyLamino-(Cl-C 4 )-aLkyl, 0 Q(Cl-C 4 Ikoxyc arbonyL amino-( C '-C 4 IkyL, (C6-CI 2 )-aryL-(CC-C4)-aLkoxycarbonyLamino-(Cl-C 4 )-aL kyL,

I(C

6 -Cl 2 )-aryl-(Cl-C 4 )-aLkyLamino-(Cl-C 4 )-aLkyL,

(C

1 -C 4 )-al k y am in o C -C4) 1k yLI di-(Cl-C 4 )-aL kyLamino-(Cl-C 4 )-aLkyL, guanidcino-(Cl-C 4 )-aLkyL, imidazoLyL, indoLyL,

(C

1

-C

4 )-aLkyLth io, (Cl-C 4 )-aLkyLthiO-(Cl-C 4 )-aLkyL, which can be substituted in the aryL moeity as described above for aryL,

(C

6 -Cl 2 )-aryt-(Cl-C 4 )-aLkyLthio which can be substituted in the aryL moeity as described above for aryL, 7 carboxyL-(C-C 4 )-aLkyt, carboxyL, carbamoyL, carbamoyL-(Cl-C4)-aLkyL, Cl -a Ik x yca rbony 1- C a Ik yL (C6-Cl2)-aryLoxy-( C -C 4 )-aLkyL which can be substituted in the aryL moeity as described above for aryL, or

(C

6

-C

12 )-aryL-(Cl-C 4 )-aLkoxy which can be subistituted in the aryl moeity as described above for aryL, R6denotes hydrogen, alkyl having 1 6 carbon atoms, aLkenyl having 2 6 carbon atoms, aLkynyl having 2 6 carbon atoms, cycLoaLkyt having 3 9 carbon atoms, cycLoalkenyL having 5 9 carbon atoms,

(C

3

-C

9 )-cycLoaLkyL-(Cl-c4)-aLkyL,

(C

5 -Cg) c y c toa Iken yI-(CC C 4)-a 1k y optionally partially hydrogenated aryL which has 6 -12 carbon atoms and can be substituted as dlescribed above f or R,

(C

6 -Cl 2 )-aryL-(Cl-C 4 )-aL kyL or (C 7 -C 13 )-aroyL-

(C

1 or C 2 )aLkyL, each of which can be substituted as the preceding aryL, mono- or bicycLic, optiornaLty partially hydrogenated heteroaryL which has 5 7 or 8 10 ring atoms respectively, 1 to 2 of these ring atoms being sulfur or oxyger; atoms and/or 1 to 4 of these ring atoms being nitrogen atoms, and can be substituted as the preceding aryL, or the optionally protected side chain of a naturaLLy occurring as-amino acid R 6

-CH(NH

2

)-COOH,

R

7 and R 8 are identical or different and denote hydrogen, aLkyL having 1 6 carbon atoms, aLkenyL having 2 6 carbon atoms, di-(Cl-C 4 )-aLkylamino-(Cl-C 4 )-aLkyL, (Cl-CS)-aLkanoytoxy-(Cl-C4)-aLkyL, (Cl-C 6 )-atkoxycarbonyLOXY-(C 1

-C

4 )-a4kyL, -t 8

(C

7 -Cl 3 )-aroyLoxy-(Cl-C 4 )-aLkyt,

(C

6 -Cl 2 )-ary~oxycarbonyLoxy-(Cl-C 4 )-aLkyL, aryl having 6 12 carbon atoms, (C 6 C12)- a -y L-(C C 4)-81ky 1,

(C

3

-C

9 )-cycLoaLkyL or (C3-C 9 )-cycLoaL kyL-(Cl-C 4 )-aLkyL and R 9 and Rio have the abovementioned meaning, pref erably those ACE inhibitors of the formuLa V in which n is 1 or 2, R 5denotes (Cl-C 6 )-aLkyL, (C 2

-C

6 )-aLkenyL, (C 3

-C

9 cycLoaLkyL, amino-(C1-C 4 )-aLkyL (C 2

-C

5 )-acyLamimo- (Cl-C 4 )-aLkyL, (C 7 -Cl 3 )-aroyLamino-(C 1

-C

4 )-aL kyL, (C 1

-C

4 )--alkoxycarbonyLamino-(C 1 -C4)-aLkyL, (C 6 -C 12)a r y1- (Cl- C 4)-aIk o xy carbon y Iamino (Cl- C4~) -81k> 1

(C

6 -Cl 2 )-aryL which can be mono-, di- or trisubstituted by (Cl-C 4 )-aLkyL, (C 1

-C

4 )-alkoxy, hydroxyl, halogen, nitro, amino, (CI-C 4 )-aLkyLamino, dj-(Cl-C 4 aLkyLamino and/or methylenedioxy or 3-indloLyl, in particular methyt, ethyl, cyctohexyL, tert.-butoxycarbonyL- 0am ino-(Cl-C 4 IkyL, benzoyLoxycarbony~amino-( C 1

-C

4 aLkyL or phenyL which can be mono- or dlisubstituted, or in the cas5e of methoxy trisubstituted, by phenyl, (Cl-C 2 )-A4kyL, (C 1 or C 2 )-aLkoxy, hydroixyl, fluorine, chicrine, bromine, amino~, (Cl-C 4 )-aLkyLamino, di-(CI-C 4 )-aLkyLamino, nitro and/or methy- Lened ioxy, R 6 denotes hydrogen or (Cl-C 6 )-aLkyL which can optioQnally be substituted by amino, CCI-C6)-acyLamino or ~'-~benzoyLamino, (C 2

-C

6 )-aLkenyL, (C, 3

-C

9 )-cYctoaLkyL,

(CS-C

9 )-cycLoaL kenyL, (C3-C7)-cycLoaLkyL-(C 1 -C4)aLkyL, CC 6 -Cl 2 )-aryL or partially hydrogenbated ary-L, ,dach of which can be substituted by (Cl-C 4 )-aLkyL,

(C

1 or C 2 )-aLkoxy or haLogen, (C6-Cl 2 )-aryL-(Cl to C4)-aLkyL or (CC13)-aroyL-(Cl-C2)-akyL, both of which can be substituted in the aryL radical as dlofined above, a mono- or bicyclic heterocycLe radlical 9 having 5 to 7 or 8 to 10 ring atoms respectively, 1 to 2 of these ring atoms being sulfur or oxygen atoms and/or 1 to 4 of these ring atoms being nitrogen atoms, or a side chain of a naturally occurring, optionally protected, a-amino acid, but in particular hydrogen, (C 1

-C

3 -alkyl, (C 2 or C 3 )-alkenyL, the optionally protective side chain of lysine, benzyL, 4-methoxybenzyL, 4ethoxybenzyl, phenethyl, 4-aminobuty or benzoylmethyl, R and R denote identical or different radicals hydrogen,

(C

1

-C

6 )-alky, (C2-C6)-alkeny or (C 6

-C

12 aryl-(C 1

-C

4 )-alky, but in particular hydrogen,

(C

1

-C

4 )-alky or benzyl, and R9 and R 10 have tht abovementioned meaning, in particular those ACE inhibitors of the formula V in which n is 2, R denotes phenyl, R denotes methyl,

R

7 and R denote identical or different (C 1 -C6)-aLky radicals or (C 7

-C

10 )-arakyl radicals such as benzyl or nitrobenzyl, and R and R 0 together represent a radical of the formula 2 0 j P

I

-LCH2 Jm in which i, denotes 0 or 1, p denotes 0, 1 or 2, and X denotes -CH 2

-CH

2 -CH2- or -CH=CH-, it also being possible for a 6-ring formed with X to be a benzene ring.

Here and hereinafter, aryl is to be understood preferably to be optionally substituted phenyl, biphenylyl or naphthyL. A similar statement applies to radicals derived from aryl, such as aryloxy and arylthio. Aroyl is particularly understood to be benzoyl. Aliphatic radicats can P"1~~ rp ii be straight-chain or branched.

A mono- or bicyclic heterocycle radical having 5 to 7 or 8 to 10 ring atoms respectively, 1 to 2 of these ring atoms being sulfur or oxygen atoms and/or 1 to 4 of these ring atoms being nitrogen atoms, is understood to be, for example, thienyl, benzolblthienyl, furyl, pyranyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrim idinyl, pyridazinyl, indazolyl, isoindolyl, indolyl, purinyl, quinolizinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, c nnolinyl, pteridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl.

It is also possible for the radicals to be partially or completely hydrogenated.

Naturally occurring a-amino acids are described in, for ex-.

S 15 ample, Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), vol. XV/1 and XV/2.

SIf R represents a side chain of a protected naturally S" occurring a-amino acid such as, for example, protected Ser, Thr, Asp, Asn, Glu, Gin, Arg, Lys, Hyl, Cys, Orn, Cit, Tyr, Trp, His or Hyp, preferred protective groups o are the groups customary in peptide chemistry (cf. Houben- Weyl, vol. XV/1 and XV/2). In the case where R 1 denotes the protected side chain of lysine, the known amino pro- :O tective groups are preferred, but in particular Z, Boc or (C1-C6)-alkanoyl. 0-protective groups suitable for tyrosine are preferably (C 1

-C

6 )-alkyl, in particular methyl or ethyl.

ACE inhibitors of the formula V can be prepared by reacting together their fragments in a suitable solvent, where appropriate in the presence of a base and/or of a coupling auxiliary, where appropriate reducing unsaturate compounds which are produced as intermediates, such as Schiff's bases, and eliminating protective groups whit have been temporarily introduced for the protectior reactive groups, and converting the resulting compt where appropr iate, into tilei r phys iolog ical ly tolerated It is possible to react compounds of the formula VI with compound9 of the formula VII in thc said manner.

ROOCH--H HOOC-CH-NH-4jH- (CH 2 )n R R R R COOR The reaction of these compounds can be carried out, for example, in analogy to known peptidle ctj~pLing processes in the presence of coupling auxiliaries such as carbodiimides (for example diqycLohexyLcarbodiimide), diphenyLphosphoryL azide,; aLkanephosphoric anhydrides, diaLkyLphoc-!.h in ic anhydr ides or NN-succ in imidlyL carbonates in CH3CN,Amino groups in compounds of the f ormul a VI can be activated with tetraethyL dliphosphite. The compounds of the formuLa VII can be converted into active esters (for example with 1-hydroxybenzotriazoLe), mixed anhydrides (for example with chLoroformic esters), azides or carbodiimidle derivatives, and thus be iectivated (cf.

Schr~cder, Ldbke, The Peptidles, volume 1, New York 1965, pages 76-136).

It is, Likewise possible to react compounds of the formula VIII with compounds of the formula VIII with the formation of compounds of the formula V, 3OOC-CH-N-C-CH-Y I 2CH-(CH 2) n- (VIII) (VIII) iri whch ;,ither Yl represents amino and Y 2 represents a Leaving group, or Y 1 represents a Leaving gr'oup, and Y represents amillo. Examples of suitable Leaving g-oups are CL, Br, 1, aLkyLsuLfonyLoxy or a,,yLsuLfonyLoxy.

12 Alkylations of this type arf advantageously carried out in water or in an organic solvent in the presence of a base.

Furthermore, compounds of the formula IX can be condensed with compounds of the formula X R OOC-CH-N-- C-C=Q 1 Q2C-(CH2) -R R 10 R6

COOR

7 (IX)

(X)

in which either Q 1 represents amino hydrogen and Q2 represents oxo, or Q represents oxo and Q2 represents amino hydrogen. The condensation is advantageously S 10 carried out in water or in an organic solvent such as a «0 ft S. lower alcohol, in the presence of a reducing agent, such #000 oo° as NaBH 3 CN, compounds of the formula V being obtained directly. However, it is also possible to reduce the So Schiff's bases or enamines produced as intermediates, where appropriate after previous isolation, with the formation of compounds of the formula V, for example by Shydrogenation in the presence of a transition metal 0 catalyst.

0 O .Finally, reaction of compounds of the formula IX (Q 1 H

NH

2 with compounds of the formula XI, or their reaction with compounds of the formulae XII and XIII, also result in compounds of the formula V (n 2),

R

7

OOC-CH-CH-CO-R

(XI)

7 5

OCH-COOR

7 R -CO-CH 3 (XII)

(XIII)

i i 13 the Schiff's bases produced as intermediates being reduced, and a carbonyl group being converted into methylene by reduction.

In the abovementioned formulae VI XIII, R5-R 10 and n are as defined in formula V. Protective groups introduced temporarily to protect reactive groups not involved in the reaction are eliminated in a manner known per se after the reaction is complete (cf. Schroder, Libke, loc.

cit., pages 1 75 and 246 270).

Orally active ACE inhibitors are advantageous, such as, for example, rampril, enalapril, captopril, lisinopril, perindopril, Lilazapril, RHC 3659, CGS 13945, CGS 13928C, CGS 14824A, CI-906, SCH 31846, zofenopril, fosenopril, alacepril and others. Orally active ACE inhibitors are described in, for example, Brunner et al., J. Cardiovasc.

Pharmacol. 7 (Suppl. I) E19853 S2-S11.

The ACE inhibitors of the formula III

H

N (S) CC H2 (III) CH NH H CH 2

CH

CH

3

COOR

in which R denotes hydrogen, methyl, ethyl or benzyl, which are discloseo in European Patent A-79,022 are preferred, in particular the compound of the formula III in which R denotes ethyl (ramipril).

The ACE inhibitors of the formula IV

COOH

(S)

H N NH CH CH (IV) CH3 COR4 0 3 14 in which R denotes hydrogen, (C 1

-C

4 )-alkyl or benzyl, which are disclosed in European Patent A-84,164, are also preferred, in particular the compound of the formula IV in which R 4 denotes ethyl.

Thus, preferred compositions according to the invention are those which contain a compound of the formula IV with

R

4 ethyl together with piretanide or furosemide, but in particular those which contain ramipril together with piretanide and which contain ramipril together with furosemide.

The combination of ACE inhibitors and loop diuretics effects a potent and persistent lowering of blood pressure and can thus be used for the treatment of high blood pressure of various etiologies. It is a particularly interesting fact that there is not an additive behavior of the actions of the two components; on the contrary, a synergistic effect is observed. In spontaneously hypertensive rats there is a lowering of blood pressure with the combination even when it contains doses of an ACE inhibitor, such as ramipril, which alone have no effect, when they are combined with doses of a loop diuretic, such as piretanide, which alone have no diuretic effect (subdiuretic doses). This shows that loop diuretics, in particular compounds of the abovementioned formula I, are able to stimulate the renin-angiotensin system without showing a divretic and saluretic effect. No such effect is achieved with compounds of the hydrochlorothiazide type.

For the reasons mentioned, the composition according to the invention is superior to the individual components for the treatment of high blood pressure, since it allows smaller doses of the components to be administered, and thus reduces any toxicological problems there may be.

The invention also relates to a process for the preparation of a composition of this type, which comprises conversion into a suitable form for administration of a) an angiotensin converting enzyme inhibitor or its physiologically tolerated salt, and b) a loop diuretic or its physiologically tolerated salt, together with physiologically acceptable vehicles and, where appropriate, other auxiliaries or additives.

The invention furthermore relates quite generally to products containing a) an angiotensin converting enzyme inhibitor or its physiologically tolerated salt, and b) a loop diuretic or its physiologically tolerated salt, preferably in a subdiuretic dose, as a combination product for concurrent, separate or sequential administration for the treatment of high blood pressure.

The ratio by weight of ACE inhibitor: loop diuretic in the said compositions and products varies depending on the activity of the active compounds, preferably between 1 and 1 500. For ramipril piretanide for example, A B preferably varies between 4 1 S i and 1 10, in particular between 2 1 and 1 3. In contrast, with ramipril furosemide the ratio A C is preferably 1 1 to 1 200, in particular 1 4 to 1 By reason of their pKa value the loop diuretics of the formula I (pK a of furosemide: 3.8) form salts with ACE inhibitors of the formula V, the compound of the formula t I 4 16 I being converted into its cation with protonation of the NH group adjacent to CHR 6 in the compound of the formula V. If the compound of the formula V (R and/or R 8

H)

is in the form of a zwitterion, a carboxylate group is protonated.

Hence the invention also relates to a salt of a loop diuretic of the formula I with an ACE inhibitor, and to pharmaceutical compositions and products which contain such a salt of a compound of the formula V. If necessary, the said compositions and products can additionally contain a loop diuretic of the formula I in the free form, or its physiologically tolerated salt, or a ACE inhibitor in the free form, or its physiologically tolerated salt.

Preferred salts of compounds of the formula I are those 0 15 with compounds of the formula III or IV, in particular a those of piretanide or furosemide with ramipril or a compound of the formula IV with R ethyl.

The salts of compounds of the formula I with compounds of the formula V are prepared by dissolving stoichiometric S 20 amounts of the reactants in a suitable solvent, and depositing the salts in solid form by concentration, cooling or addition of another solvent in which they are less 4 4 soluble. The salts can be processed to give compositions or products in the manner described above.

The doses of the ACE inhibitor and of the loop diuretic in the compositions or products according to the invention are each preferably selected so that the ACE inhibitor and/or the loop diuretic would alone show no effect or not a full effect. Thus, a dose of the loop diuretics which is far below the ED 5 0 for instance at its threshold diuretic dose, suffices. The sufficient doses of the ACE inhibitors as components are those which are at approximately the minimum dose adequate for plasma ACE inhibition r 17 (for determination, see: Metzger et at., Arzneim.-Forsch./ Drug Res. 34 1402, 1403); thus, they can be below those which are required for an acute Lowering effect on blood pressure when an ACE inhibitor is used alone.

For the use according to the invention in mammals, preferably in humans, for example the doses of an ACE inhibitor of the abovementioned formula III or IV range, for example, from 0.05 to 2 mg/kg/day, and those of a diuretic of the abovementioned formula I range from 0.2 to 2! mg/kg/day.

The compositions or products according to the invention can be administered parenterally or orally. The oral administration form is preferred.

o The pharmacologically utilizable combinations of the present invention and their salts can be used for the prepr i aration of pharmaceutical products which contain an efo fective amount of the active substances together with o 0 vehicles, and which are suitable for enteral and parenteral administration. Use is preferably made of tablets or gelatin capsules which contain the active compounds together with diluents, for example lactose, dextrose, a sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricants such as diatomaceous earth, talc, stearic °u a acid or its salts, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets likewise contain binders, such as magnesium aluminum silicate, starch, Sgelatin, tragacanth, methylcellulose, sodium carboxymethylicellulose and/or polyvinylpyrrolidone, and, if necessary, pigment, flavorings and sweeteners.

Injectable solutions are preferably isotonic aqueous solutions or suspensions which can be sterilized and may contain auxiliaries such as preservatives, stabilizing agents, wetting and/or emulsifying agents, solubilizers, 18 salts to regulate the osmotic pressure and/or buffer substances.

The pharmaceutical products according to the invention, which may contain, if desired, further pharmacologically valuable substances, are prepared by, for example, conventional mixing, granulating and coating processes, and contain 0.1% to about 75%, preferably about 1% to about 50%, of the active compounds.

This entails the active compounds being mixed or dissolved together with the abovementioned auxiliaries and additives in a mixing device at 5 500C and then, for example, compressed to form tablets or dispensed into gelatin capsules or ampoules.

The examples which follow serve to illustrate the present invention without the latter being restricted to them.

Example 1 Effect of the combination of ramipril and piretanide on the spontaneously hypertensive rat spontaneously hypertensive rats (Wistar-Kyoto) are attached to instruments and kept in metabolism cages during the tests. Ramipril (1 mg/kg) and piretanide (1.2 and 16 mg/kg) are administered orally in Tylose using a stomach tube. The control group received only Tylose. The amount of urine excreted after 5 hours, the sodium excretion after 5 hours and the mean arterial pressure were determined.

T l rr*rmr~rrririual Table 1 Excretion of urine over 5 hours Amount of urine (pL/100g.5h) Tylose (1 ml/kg) (1 mg/kg) (1 mg/kg) (2 mg/kg) (16 mg/kg) 460+65 760+185 900+180 1470+140 3520+405 1100+145 1545+130 3590+285 A (1 mg/kg) B (1 mg/kg) A (1 mg/kg) B (2 mg/kg) A (1 mg/kg) B (16 mg/kg) *I e Table 2 Excretion of sodium over 5 hours mNa(x+SD+SEM) (mmol/150g.5h) Tylose (1 ml/kg) 0.021+0.0009+0.003 A (1 mg/kg) 0.080+0.049 +0.016 B (1 mg/kg) 0.082+0.057 +0.021 B (2 mg/kg) 0.156+0.063 +0.022 B (16 mg/kg) 0.462+0.146 +0.052 A (1 mg/kg) B (1 mg/kg) 0.157+0.050 +0.321 A (1 mg/kg) B (2 mg/kg) 0.158+0.033 +0.012 A (1 mg/kg) B (16 mg/kg) 0.513+0.076 +0.031 The change in the mean blood pressure (MBPt) as a of the initial blood pressure (MBP

O

with time is shown in the figure. The individual lines in this figure have the following meanings:

A-

i _L U Tylose (1 mg/kg): line h A (1 mg/kg): Line a B (1 mg/kg): line b B (2 mg/kg): line c B (16 mg/kg): line d A (1 mg/kg) B (1 mg/kg): line g A (1 mg/kg) B (2 mg/kg): Line f A (1 mg/kg) B (16 mg/kg): line e Example 2 Preparation of an oral combination product from ramipril and piretanide o o °o 1,000 tablets containing 1 mg of each of A and B were o prepared using the following auxiliaries: o o 0 2 0 A 1 g B 1 g Corn starch 140 g °Go, Gelatin 7.5 g Microcrystalline cellulose 2.5 g Magnesium stearate 2.5 g A and B are mixed with an aqueous solution of gelatin.

The mixture is dried and milled to form granules. Micro- 0 00 oo°' crystalline cellulose and magnesium stearate together with corn starch are mixed with the granules. The resulting granules are compressed to form 1,000 tablets, each tablet containing 1 mg of each of A and B.

Example 3 Preparation of a parenteral combination product of ramipril and piretanide 21 The preparation of an injection solution for the treatment of hypertension is described below: A 0.25 g B 0.25 g Methylparaben 5 g Propylparaben 1 g Sodium chloride 25 g Water for injections 5 L A, B, the preservatives and 'dium chloride are dissolved in water for injection and male up to 5 L with water for injections. The solution is sterilized by filtration and dispensed under aseptic conditions into pre-sterilized bottles which are closed with sterilized rubber caps.

Each bottle contains 5 ml of solution.

15 Example 4 oo4 Preparation of an oral combination product of ramipril and furosemide t 01000 tablets which contain 5 mg of A and 20 mg of C were prepared with the following auxiliaries: 0o 0 A 5 g C 20 g Corn starch 140 g SGelatin 7.5 g Microcrystalline cellulose 2.5 g Magnesium stearate 2.5 g.

A and C are mixed with an aqueous gelatin solution. The mixture is dried and milled to form granules. Microcrystalline cellulose and magnesium stearate together with corn starch are mixed with the granules. The resulting granules are compressed to form 1000 tablets, each tablet containing 5 mg of A and 20 mg of C,, Example Preparation of an oral combination product of enalapril and furosemide 1000 tablets containing 10 mg of D and 20 mg of C are prepared with the following auxiliaries: D 10 g C 20 g Corn starch 140 g Gelatin 7.5 g Microcrystalline cellulose 2.5 g Magnesium stearate 2.5 g D and C are mixed with an aqueous gelatin solution. The mixture is dried and milled to form granules. Microcrystalline cellulose and ianesium stearate together with corn starch are mixed with the granules. The resulting granules are compressed to form 1000 tablets, each tablet containing 10 rg of D and 20 mg of C.

Example 6 In analogy to Example 2, tablets containing 4 mg of ramipril and 1 mg of piretanide per tablet are prepared.

Example 7 In analogy to Example 2, tablets containing 0.5 mg of ramipril and 5 mg of piretanide per tablet are prepared, 23 Example 8 In analogy to Example 4, tablets containing 25 mg of ramipril and 30 mg of furosemide per tablet are prepared.

Example 9 In analogy to Example 4, tablets containing 1 mg of ramipril and 25 mg of furosemide per tablet are prepared.

L R

Claims (6)

1. A pharmaceutical composition containing a) an angiotensin converting enzyme inhibitor or its physiologically tolerated salt described by the general formula V in which R 0 OC CH N C CH NH CH (CH 2 n -R (V) 9 1 II 1 6 7 R9 R00 R COOR n is 1 or 2 S° R 5 denotes hydrogen, an optionally substituted S° aliphatic radical having 1 8 carbon atoms, an optionally substituited alicyclic radical 0 C 0 0-- o having 3 9 carbon atoms, an optionally substituted aromatic radical having 6 12 carbon atoms, an optionally substituted araliphatic radical having 7 14 carbon atoms, an optionally substituted alicyclic-aliphatic radical having 7 14 carbon atoms, aa a radical OR a or SR', in which R a represents an optionally substituted aliphatic o ,radical having 1 4 carbon atoms, represents an optionally substituted aromatic radical having 6 12 carbon atoms, or an optionally o substituted heteroaromatic radical having I 12 ring atoms, R denotes hydrogen, an optionally substituted aliphatic radical having 1 6 carbon atoms, an optionally substituted alicyclic radical having 3 9 carbon atoms, an optionally substituted alicyclic-aliphatic radical having 4 13 Jarbon atoms, an optionally substituted aromatic radical having 6 12 carbon atoms, ~1- an optionally substituted araliphatic radical having 7 16 carbon atoms, an optionally substituted heteroaromatic radical having 5 12 ring atoms, or the side chain, protected where necessary, of a naturally occurring a-amino acid, R 7 and R 8 are identical or different and denote hydrogen, an optionally substituted aliphatic radical having 1 6 carbon atoms, an optionally substituted alicyclic radical having 3 9 carbon atoms, an optionally substituted aromatic radical having 6 12 carbon atoms, an optionally substituted araliphatic radical having 7 16 carbon atoms, and R 9 and R 10 together with the atoms carrying them, form a heterocyclic bi- or tricyclic ring S system 4 15 carbon atoms, and b) a loop diuretic or its physiologically tolerated salt in a subdiuretic dose.

2. A composition as claimed in claim 1, wherein the loop diuretic has the formula I R 2 R R 3 H NO OOH in which R 1 denotes chlorine or phenoxy -0 4 26 R 2 denotes hydrogen, pyrrolidino or n-butylamino, and R3 denotes hydrogen or 2-furylmethylamino. A composition as claimad in one of claims 1-2, the loop diuretic has the formula II or III

3. wherein V H 2 NO 2 S COOH I-CH 2 H 2 NO1 2 S OO1

4. A composition as claimed in one of claims 1-3, wherein the angiotensin coverting enzyme inhibitor has the forula III H COOH (S) CH. (S) NHi CH- CH 2 H2- 0OR (I II in which R denotes hydrogen, methyl, ethyl or ,enzyl, or the formula IV 'N cooH. -N (S (S) S-CH NH CHI CH- CH 8~H (-04 2 2 IV) r I rx u 27 in which R 4 denotes hydrogen, (C 1 -C 4 )-alkyl or benzyl. A composition as claimed in one of claims 1-4, wherein the angiotensin converting enzyme inhibitor has the formula III or IV in which R or R 4 denotes ethyl.

6. A process for the preparation of a composition as claimed in one of claims 1-5, which comprises conversion into a suitable form for administration. a) an angiotensin converting enzyme inhibitor or its salt and b) a loop diuretic or its physiologically tolerated salt together with physiologically acceptable vehicles and, where appropriate, other auxiliaries or additives. 0 o o 00 0 0 a 0 4 00 A salt of a) an angiotensin converting enzyme inhibitor and b) a loop diuretic of the formula I in which R. R 2 and R 3 are defined as in claim 2. 1" I I 1 r ri

8. A in claim 7 converting formula I. process for the preparation of a salt as claimed which comprises, reaction of an angiotensin enzyme inhibitor with a loop diuretic of the DATED this 26th day of January, 1990 HOECHST AKTIENGESELLSCHAFT 4, I WATERMARK PATENT TRADEMARK ATTORNEYS, "The Atrium" 290 Burwood Road Hawthorn, Victoria, 3122 AUSTRALIA DBM/KJS: JJC (3/11) o 4, 4, Ka--